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Corralling Pancreatic Cancer through Epigenetic Reprogramming
Author(s) -
Evans Ronald M.,
Antal C.,
Truitt M.,
Liang G.,
Sherman M.,
O'Dwyer P.,
Drebin J.,
Downes M.,
Tuveson D.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.250.1
Subject(s) - biology , stromal cell , cancer research , epigenetics , tumor microenvironment , reprogramming , pancreatic cancer , calcitriol receptor , microbiology and biotechnology , cancer , cell , receptor , genetics , gene , tumor cells
Pancreatic ductal adenocarcinoma (PDAC) occurs in the context of an exuberant desmoplastic response that produces a ‘living chimera’ of tumor and activated stromal components. We have shown that the vitamin D receptor (VDR) is expressed at high levels in activated human pancreatic stellate cells (PSCs) and, in response to ligand, reprograms PSCs to the quiescent state. In vivo, a synthetic VDR agonist (Cal) similarly remodels tumor stroma, enhancing the anti‐tumor effects of gemcitabine and reducing tumor growth. We will describe the use of a three‐dimensional culture system to dissect the adaptive impact of the stromal secretome on the cancer cell. This integrative approach identified the rapid mobilization of more than a dozen gene networks (cell cycle, steroid biosynthesis, metabolic pathways, DNA replication, etc.), as well as a commensurate adaptive metabolome. In examining chromatin adaptation, our work uncovers a molecular ‘ and‐gate’ such that tumor activation is the consequence of mutant Ras and the TME. To mediate this molecular handshake, we find that BRD2 (but not BRD4) in the epithelial compartment transduces stromal cues at the genomic level. This response is blocked by the BET bromodomain inhibitor JQ1 and reduces pancreatic tumor growth in vivo . Collectively, we describe a novel molecular connection between the stroma and a driver oncogene that offers new insights into the role of the TME in the treatment of ras‐driven tumor. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .